The development of dopamine D2-receptor selective antagonists

This paper reviews the development of 2,6-dioxygenated benzamides such as remoxipride and various salicylamides (raclopride, eticlopride) into other types having a 5,6-dioxygenated benzamide moiety. The structural, conformational and stereochemical aspects on the structure-activity relationships are discussed. The three side chain classes (S)-2-pyrrolidinylmethyl-, (R)-2-pyrrolidinylmethyl- and 4-piperidinylbenzamides have different requirements on aromatic substituents and side chain conformations. Besides, the latter two types demand lipophilic nitrogen substituents (arylalkyl) for dopamine D2 receptor affinity. This indicates that they have different pharmacophoric requirements that might prove useful in investigations on dopamine D2 receptor subtypes. The 3-substituted 5,6-dimethoxysalicylamides (e.g. FLB 463 and NCQ 298) and the 3-substituted 5,6-dimethoxybenzamides (e.g. FLB 457 and NCQ 219) constitute highly potent and selective dopamine D2 antagonists in vitro as well as in vivo. Both types of benzamides have been developed as radioligands for receptor binding (125I, 3H), PET (11C, 18F) and SPECT (123I) studies which fully take advantage of the favourable properties. Thus, NCQ 298, NCQ 115, FLB 457 and NCQ 616 are such potent and selective ligands, which are suitable for further receptor characterization and studies on dopamine D2 mediated responses.